Abstract Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by pathogenic autoantibodies that potentiate inflammatory injury in tissues such as skin, lungs and kidneys. One of the most prevalent, but perhaps least understood aspects of SLE; however, is the fact that up to 75% of patients develop neuropsychiatric symptoms, a condition referred to as central nervous system (CNS) lupus. In general, the cellular basis for mental health disorders is not well understood. CNS lupus symptoms are extremely varied and complicated by the systemic nature of the disease; therefore, little progress has been made to understand this aspect of the disease. The molecular mechanisms of CNS lupus are a major gap in the lupus field preventing the development of effective therapeutic approaches for CNS lupus patients. Interestingly, CNS lupus patients can show reduced grey matter volume, suggestive of neuron or synapse loss; however, the mechanisms underlying neuron and synapse loss in lupus have yet to be fully explored. We looked to other CNS diseases for clues as to the mechanisms of CNS lupus. In Alzheimer's disease, synapse loss is one of the earliest events in the disease and microglia have been identified as major mediators of synapse loss in Alzheimer's via changes in microglia phagocytic capacity and activation of the classical complement cascade. In our own study using a murine lupus model, we found a significant increase in the frequency of activated microglia relative to normal wild type littermates. Moreover, microglia could be found engulfing neuronal material similar to what is observed during early development where microglia are important in synaptic pruning and in Alzheimer's mouse models. Gene expression analysis of activated microglia isolated from the brains of lupus mice identified significant upregulation of interferon stimulated genes (ISG) and a general pattern of gene expression associated with changes in microglia function. Given that elevated type I interferon is very common in lupus patients, we hypothesized that this cytokine may play a critical role in CNS lupus. In support of this idea, treatment in vivo with anti-interferon receptor antibody protected against reactive microglia and engulfment of neuronal material. This proposal tests our hypothesis that peripheral cytokines, specifically type I interferon, trigger a microglia-dependent synaptic pruning program leading to damaging elimination of neuronal material that could represent a treatable pathway in CNS lupus. Two aims are proposed to test our hypothesis. Specific aim 1: Test the hypothesis that SLE stimulates changes in microglia that promote hyperphagocytosis and synapse loss. Specific aim 2: Test the hypothesis that elevated type I interferon underlies CNS dysfunction in SLE. Demonstrating that microglia are stimulated by inflammatory cytokines in CNS lupus to initiate a synaptic pruning program is transformative and may generate novel treatments for this enigmatic disorder.